Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

The Wnt signaling pathway is known to play pivotal roles in driving tumor growth and therapy resistance, however, to date there are no clinically approved Wnt inhibitors. Candidate agents have shown on-target toxicities (gastrointestinal and bone) both preclinically and in phase 1 trials. Li and colleagues report significant antitumor efficacy using a novel small molecule CK1α activator, SSTC3, in Wnt-driven colorectal tumor models. SSTC3 attenuated growth of metastatic patient-derived KRAS mutant colorectal cancer xenografts, for which few therapeutic options exist. Importantly, unlike most other classes of Wnt inhibitors, SSTC3 showed only minor on-target gastrointestinal toxicity at its efficacious dose. They further demonstrated that the differential abundance of the drug target, CK1α, drove this expanded therapeutic window. Therefore, CK1α activators, such as SSTC3, represent the first class of Wnt inhibitors to preferentially target Wnt-driven cancerous tissue.Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, et al. Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors. Sci Signal 2017;10. doi: 10.1126/scisignal.aak9916.The PI3K/AKT/mTOR pathway is one of the main growth regulatory pathways that is frequently activated in many types of cancer. Creighton and colleagues determined PI3K/AKT/mTOR pathway activation across 11,219 human cancers representing 32 cancer types. Using The Cancer Genome Atlas–based whole-exome sequencing, whole-genome sequencing, DNA copy number analysis, and reverse-phase protein array analysis of 166 proteins with phosphorylation status for 56, the authors correlated genetic mutations to functional changes in pathway activity. Unexpectedly, some tumor types displayed high mTOR pathway activity without associated canonical genetic or genomic alterations. These tumors were enriched for IDH1 and VHL mutations. While these genes have not commonly been associated with the PI3K/AKT/mTOR pathway, this study suggests that defects in IDH1 and VHL induce pathway activation. Consequently, inhibitors of the PI3K/AKT/mTOR pathway may be efficacious in patients with IDH1 and VHL mutant tumors.Zhang Y, Kwok-Shing Ng P, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell 2017;31:820–32.Medulloblastoma is the most common malignant brain tumor in children. TP53-mutated SHH and MYC-amplified Group 3 represent very high-risk medulloblastoma subtypes. Cook Sanger and colleagues established CIS-derived candidate cancer genes in a Sleeping Beauty–based model of medulloblastoma. CDKN2a/p16 was identified as a novel target, suggesting CDK4/6/cyclin D/Rb as a targetable pathway in medulloblastoma. The authors leveraged this in silico analysis to study the efficacy of palbociclib, a CDK4/6 inhibitor for the treatment of both SHH- and MYC-amplified Group 3 medulloblastoma. Palbociclib suppressed Rb phosphorylation, caused G1 arrest, and led to regression in subcutaneous patient-derived xenografts of both SHH- and MYC-amplified Group 3 tumors. A trial of palbociclib in intracranial MYC-amplified Group 3 models revealed a significant survival advantage, providing preliminary evidence of brain penetration. This study provides subgroup-specific evaluation of CDK4/6 inhibition in highest risk medulloblastoma as well as preclinical studies to guide clinical trials.Cook Sangar ML, Genovesi LA, Nakamoto MW, Davis MJ, Knoblaugh SE, Ji P, et al. Inhibition of CDK4/6 by palbociclib significantly extends survival in medulloblastoma patient-derived xenograft mouse models. Clinical Cancer Research; Published OnlineFirst June 21, 2017; doi: 10.1158/1078-0432.ccr-16-2943.The altered expression of oncogenes and tumor suppressor genes plays a critical role in cancer progression. Shahi and colleagues demonstrate that the axonal guidance molecule, semaphorin 3B (SEMA3B), suppresses progression and metastasis in breast cancer cells. From analysis of published data, the authors observed that lower expression of SEMA3B correlated with invasive stages and a poor survival in breast cancer. A positive correlation between SEMA3B and the GATA3 transcription factor was noted. They demonstrated that GATA3 binds to the SEMA3B promoter to directly regulate SEMA3B expression. Through gain- and loss-of-function studies in breast cancer cell lines, the authors showed that the inhibitory effects of GATA3 on proliferation and migration were dependent on intact SEMA3B expression. Abrogation of SEMA3B in the face of GATA3 overexpression did not rescue the tumor suppressor activities of GATA3. These studies identify SEMA3B as a significant component of the GATA3 signaling axis in mammary epithelial cells.Shahi P, Wang CY, Chou J, Hagerling C, Gonzalez Veloso H, Ruderisch A, et al. GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. Oncogene; Published online June 5, 2017; doi: 10.1038/onc.2017.165.Radioresistance of locoregional head and neck squamous cell carcinoma (HNSCC) drives treatment failure and death. While human papilloma virus (HPV)-positive HNSCC is sensitive to radiation, HPV-negative HNSCCs are generally radioresistant. Skinner and colleagues observed coordinated upregulation of PI3K, Axl, and PD-L1 in a radioresistant HPV-negative HNSCC cell line. Pharmacologic and genetic inhibition of PI3K and Axl downregulated PD-L1 expression in vitro. The association among PI3K, Axl, and PD-L1 was validated extensively in three separate HNSCC radiation-treated patient cohorts integrating multiple mRNA and protein platforms. Expression of PD-L1 correlated with local control and, in some cases, survival. How PI3K and Axl regulate PD-L1, and how PD-L1 confers radioresistance remain to be determined. However, this report supports selecting HPV-negative HNSCC patients based on PD-L1 expression and targeting the PD-1/PD-L1 axis in combination with radiation in prospective clinical trials.Skinner HD, Giri U, Yang LP, Kumar M, Liu Y, Story MD, et al. Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer. Clin Cancer Res 2017;23:2713–22.The super-enhancer landscape is a determining factor for fate specification of tumor cells. Van Groningen and colleagues used both isogenic patient-derived and established neuroblastoma cell lines to demonstrate that most tumors consist of at least two epigenetically and transcriptionally distinct cell types that can interconvert—undifferentiated mesenchymal (MES) and committed adrenergic (ADRN) cells. Both cell types displayed a characteristic super-enhancer landscape that drove expression of cell type-specific transcription factors. Overexpression of one such transcription factor, PRRX1, resulted in the partial dedifferentiation of ADRN to MES cells. Further, mesenchymal cells were more chemoresistant than ADRN cells and appeared to be enriched in relapsed tumors. This study shows that variations in super-enhancer landscapes play a major role in fashioning tumor heterogeneity in neuroblastoma, with enrichment of specific phenotypes in therapy resistance.van Groningen T, Koster J, Valentijn LJ, Zwijnenburg DA, Akogul N, Hasselt NE, et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet 2017; Published online June 26, 2017; doi: 10.1038/ng.3899.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.